Formulation of nitrogen mustard

ABSTRACT

Compositions of matter comprising a substituted cyclodextrin and cytotoxic compound, especially cytotoxic drugs such as antibiotic, anti-fungal and anti-neoplastic, drugs are claimed. The compositions cause significantly less ulceration compared to the same formulation of cytotoxic compound without cyclodextrin compound when extravasated. The compositions may also cause less vascular irritation compared to the same formulation of cytotoxic compound without cyclodextrin when administered intravenously without extravasation. Compositions of matter comprising watersoluble cytotoxic agents, especially anticancer drugs and anti-ulceration effective or anti-irritatioin effective amounts of cyclodextrin compounds are also claimed. Methods for reducing the likelihood of ulceration and or irritation when administering the compositions according to the invention are also disclosed and claimed.

[0001] This application is a continuation-in-part application of U.S.patent application Ser. No. 08/1116,724 filed Sep. 3, 1993, which was acontinuation-in-part application of U.S. patent application Ser. No.09/911,664 filed Jun. 19, 1992, now abandoned.

FIELD OF THE INVENTION

[0002] The present invention relates to improved pharmaceuticalformulations.

BACKGROUND OF THE INVENTION

[0003] Many compounds that can be injected intravascularly into animaland human patients for a beneficial effect have the undesirablehazardous side effect of causing ulceration at the injection site as aresult of extravasation. Extravasation is strictly defined as theforcing of fluid out of a blood or lymph vessel into the surrounding orperivascular tissue. More broadly defined, extravasation may be said tooccur when an injection solution and blood or serum combined with aninjection solution leaks out of a blood vessel during intravascularadministration of the solution or subsequent thereto, at the site ofinjection, or when the injection solution is accidentally injected intotissue surrounding a blood vessel. Such extravasation may occur as aresult of accidentally failing to properly insert a needle for theintravascular administration of a solution into the lumen of a bloodvessel. It may also occur by accidentally inserting a needle entirelythrough a blood vessel intended for intravascular administration. Inaddition, leakage of solution from a blood vessel may occur if a bloodvessel is too small for the rate and volume of injection solution beinginjected into the blood vessel. Lastly, leakage of solution from a bloodvessel may occur if the blood vessel has been damaged or eroded by priorinjection or other trauma.

[0004] Extravasation of certain intravasuclarly administered compoundsmay lead to formation of a deep, spreading and painful ulcer which mayrequire surgical extirpation of the affected tissue. Skin grafting isfrequently required to repair and reconstruct the resulting wound.Another complication of such intravascularly administered compounds isthat they are irritants causing irritation of the lining of the bloodvessel into which they are injected. This irritation may be accompaniedby pain at the site of injection or along the length of the bloodvessel. In addition the irritation may lead to reduced patency of theblood vessel and in some cases may induce the formation of blood clotsin the affected blood vessel leading to a risk of gangrene or emboli.

[0005] Not all injection solutions cause ulceration as a result ofextravasation; however; many pharmaceutical compounds injected forparticular chemotherapeutic effects in many therapeutic categories havethis presently unavoidable side effect. Pharmaceutical compounds havingthis side effect are well known to those skilled in the art ofadministration of such compounds to patients and animal subjects. Theside effects of such drugs are collected in a number of publicationincluding the Physicians Desk Reference published yearly by MedicalEconomics Data, a division of Medical Economics Company Inc., MontvaleN.J. 07645 USA and the United States Pharmacopeia Drug Informationpublished and supplemented by the Untied States Pharmacopeial Convention, Inc 12601 Twinbrook Parkway, Rockville, Md. 20852, USA. Similarvolumes are published else where in various countries of the world.

[0006] Among the pharmaceutical compounds that cause extravasationassociated ulceration are cytotoxic compounds which are administered topatients and animal subjects for the purpose of manifesting a specificcytotoxic effect. Such cytotoxic compounds include many anticancer orantineoplastic compounds. These compounds may be synthetic chemicalcompounds, such as nitrogen mustard derivatives such as mechlorethamine,plant alkaloids such as vincristine and vinblastine, alkylating agentssuch as dacarbazine and streptozocin or microbially produced andpurified or partially purified antibiotics. Cytotoxc antibiotics includethose administered as anti-cancer agents, such as mitomycin, bleomycin,daunorubicin, doxorubicin, plicamycin and dactinomycin. In additionantifungal antibiotic agents such as amphoteracin B can cause ulcerationassociated with extravasation. Furthermore, therapeutic compounds whichare not administered to achieve a specific cytotoxic effect may alsoresult in extravasation associated ulceration. For example certainsedative compounds when injected intravasculary (IV) can cause severeulceration if extravasation occurs. Such sedative compounds include butare not limited to benzodiazapine compounds including diazepam. Thus,there is a long felt need For safer formulations of injectablepharmaceutical compounds to reduce or eliminate ulceration resultingfrom extravasation.

[0007] Pharmaceutical preparations containing cyclodextrin are known.Human sex hormones including, estradiol-, progesterone- andtestosterone - hydrophilic cyclodextrin derivatives, especiallyhydroxypropyl cyclodextrin suitable for oral mucosal or rectal mucosalAdministration are disclosed in U.S. Pat. No. 4,596,795. Thesepreparations are disclosed as increasing the circulating half life ofthe hormone through elimination of absorbance via the gastrointestinaltract and consequent removal by hepatic clearance. There is nodisclosure of complexes that reduce local ulceration or irritation at aninjection site.

[0008] U.S. Pat. No. 4,727,064 disclosed pharmaceutical preparationsconsisting generally of a drug with a substantially low water solubilityand an amorphous water soluble cyclodexrin-based mixture having improveddissolution properties and absorption by the body. The solutions ofamorphous water soluble cyclodextrin are disclosed as nonirritatingtopically, and having low toxicity, both systemic and local, whenapplied parenterally. None of the amorphous cyclodextrin-drug mixturesdisclose in the specification or claims discloses a complex including adrug that causes ulceration when extravasted and there is no disclosureconcerning reduction of ulceration as a result of administering the drugin a complex with an amorphous cyclodextrin complex.

[0009] A variety of improvements in the characteristics ofpharmaceutical complexes including various cyclodextrins andcyclodextrin derivatives are disclosed in the following United Statespatents, but none of them disclose the reduction inextravasation-associated ulceration, or irritation through the formationof complexes of cyclodextrin and pharmaceutical compounds: Noda et al.,U.S. Pat. No. 4,024,223 methyl salicylate; Szejtli et al U.S. Pat. No.4,228,160 indomethacin; Hyashi et al., U.S. Pat. No.4,232,009ω-halo-PGI₂ analogs; Matsumoto et al., U.S. Pat. No. 4,351,8463-hydroxy and 3-oxo prostaglandin analogs; Yamahira et al., U.S. Pat.No. 4,353,793, bencyclane fumarate; Lipari, U.S. Pat. No. 4,383,992steroids-corticosteroids, androgens anabolic steroids, estrogens,progestagens; Nicolau, U.S. Pat. No. 4,407,795 P-hexadecyla-ninobenzoicacid sodium salt; Tuttle, U.S. Pat. No. 4,424,2093,4-diisobutyryloxy-N-{3-(4-isobuttyryloxyphenyl)-1-methyl-n-propyl]-β-phenethylamine;Tuttle, U.S. Pat. No. 4,425,336,3.4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n-propyl]-β-phenethylamine;Wagu et al., U.S. Pat. No. 4,438,106 fatty acids EPA and DHA; Masuda etal., U.S. Pat. No. 4,474,881 2-(2-fluoro-4-biphenyl)propionic acid orsalt; Shinoda et al., U.S. Pat. No. 4,478,995 acid addition salt of(2′-benzyloxycarbonyl)phenyltrans-4-guanidinomehtylcyclohexanecaboxylate; Hyashi et al., U.S. Pat.No. 4,479,944 Prostaglandin I₂ analog; Hayashi et al., U.S. Pat. No.4,479,966, 6,9-methano-prostaglandin I₂ analogs; Harada et al., U.S.Pat. No. 4,497,803 lankacidin-group antibiotic; Masuda U.S. Pat. No.4,499,085 prostoglandin analog; Szejtli et al., U.S. Pat. No. 4,524,068piperonyl butoxide; Jones, U.S. Pat. No. 4,555,504 cardiac glycoside;Uekama et al., U.S. Pat. No. 4,565,807 pirprofen; Ueda et al., U.S. Pat.No. 4,575,548 2-nitroxymethyl-6-chloropyridine; Ohwaki et al., U.S. Pat.No. 4,598,070 tripamide anti-hypertensive; Chiesi et al., U.S. Pat. No.4,603,123 piroxicam (feldene); Hasegawa et al., U.S. Pat. No. 4,608,366monobenzoxamine; Hiari et al., U.S. Pat. No. 4,659,696 polypeptide;Szejtili et al., U.S. Pat. No. 4,623,641 Prostoglandin I₂ methyl ester;Ninger et al., U.S. Pat. No. 4,663,316. unsaturated phosphorouscontaining antibiotics including phosphotrienin; Fukazawa et al., U.S.Pat. No. 4,675,395 hinokitol; Shimizu et al., U.S. Pat. No. 4,728,5093-amino-7-isopropyl-5-oxo-5H-[1]-benzopyrano[2,3-b]pyridine-3-carboxcylicacid; Shibani et al., U.S. Pat. No. 4,728,510 milk component Karl et alU.S. Pat. No. 4,751,095 aspartame.

[0010] Among the above-mentioned patents, several indicate thatcomplexes of cyclodextrin with drug substances improve side effects ofthe drug substance. Szejtli et al., U.S. Pat. No. 4,228,160 disclosedthat the frequency and severity of gastric and duodenal erosion andulceration in rats caused by indomethecin is improved in an oralformulation of a complex of β-cyclodextrin: indomethacin in a 2:1 ratio,but is not improved and in fact worsens in the same oral formulation ofa complex of β-cyclodextrin: indomethacin in a 1:1 ratio.

[0011] Shirmazu et al., U.S. Pat. No. 4,352,793 discloses that aformulation wherein bencyclane fumarate an anti-convulsive compound andβ-cyclodextrin or γ-cyclodextrin yield a complex in which the bencyclanefumarate is an inclusion compound. These complexes, when formulated as aliquid suitable for oral administration were claimed to be lessirritating in an isotonic buffered pH 7 solution when administered asdrops to the eyes of rabbits, as compared to bencyclane fumarate dropsat the same drug concentration. Shimazu et al., also discloses thatsimilar complexes dissolved in rabbit blood in vitro yielded reducedhemolysis as compared to equal concentrations of bencyclane fumaratealone mixed with rabbit blood. There was no indication that thiscompound is cytotoxic or causes ulceration or irritation of thesurrounding tissue when extravasated during or after injection.

[0012] Masuda et al., U.S. Pat. No. 4,478,811 disclose ophthalmicformulations of β- or γ-cyclodextrin complexes of the nonsteroidalanti-inflammatory compound fluoro-bi-phenylacetic acid which are lessirritating and painful than the same formulations of fluoro-bi-phenylacetic acid alone. There was no indication that this compound iscytotoxic or causes ulceration of the surrounding tissue whenextravasated during for after injection.

[0013] Shinoda et al., U.S. Pat. No. 4,478,995 disclose complexes of α-,β- and γ-cyclodextrin and acid addition salts of (2-benzyloxycarbonyl)phenyl trans-4-guanidinomehtylcyclo-hexanecaboxylate,and enzyme inhibitor having anti- gastric and duodenal ulcer activity.The complexes were administered orally and were more active inpreventing ulceration than oral administration of acid addition salts of(2′-benzyloxycarbonyl)phenyltrans-4-guanidinomehtylcyclo-hexanecaboxylate alone in solution. Nopreparation suitable for intravenous injection were disclosed and therewas no indication that this compound is cytotoxicor causes ulceration ofthe surrounding tissue when extravasated during for after injection.

[0014] Uekama et al., U.S. Pat. No. 4,565,807 discloses complexes of α-,β- and γ-cyclodextrin, pirprofen and a pharmaceutically acceptable base.Piprofen is an analgesic and anti-inflammatory compound which is bitterand can cause irritation to the gastrointestinal tract. The complexesdisclosed in the patent have improved less bitter taste and are lessgastrointestinal irritating than the un-complexed compound piprofen. Nopreparation suitable for intravenous injection were disclosed and therewas no indication that this compound is cytotoxic or causes ulcerationof the surrounding tissue when extravasated during for after injection.

[0015] Bekers, O., et al.,“Stabilization of mitomycins on complexationwith cyclodextrins in aqueous acidic media” International Journal ofPharmaceutics, 53 (1989) 239-248 describes the investigation ofstabilization of mytomycin-C and several related mitomycins by formationof a complex with cyclodextrin. The authors indicte that at the pHranges studied α- and β-cyclodextrin as sell asheptakis-(2,6,-di-O-methyl)-β-cyclodextrin and (dimethyl-β-cyclodextrinhave no influence on stabilization of mitomycin-C pH degradation.γ-cyclodextrin is reported as having measurable stabilizing effect onmitomycin in acidic media at pH above 1. There is no suggestion thatstabilization of mitomycin-C from acidic degradation in aqueous media bycomplexation with γ-cyclodextrin is or can be related to amelioration ofulceration or irritation caused by mitomycin when administered to apatient.

[0016] Bodor U.S. Pat. No. 5,024,998 and Bodor U.S. Pat. No. 4,983,586disclose a series of compositions comprising complexes of :Betahydroxypropylcyclodextrin (HPCD)-complexed to a difficult to solubilizedrug, or HPCD complexed to a drug- which has first been complexed to asepcific class of drug carriers characterized as redox drug carriers.The complex of drug and redox carrier is itself difficult to solubilizeand is highly lipophilic due to the presence of pyridine derivatives aspart of the redox carrier complex. Bodor '998 and '586 further claimthat a solution of 20 to 50% hydroxypropylcyclodextrin-and lipophilicdrug-redox carrier complex or 20 to 50% hydroxypropylcyclodextrin-andlipophilic and or water labile drug is useful in a method of “decreasingthe incidence of precipitation of a lipophilic and/or water labile drugoccuring at or near the injection site and/or in the lungs or otherorgans following parenteral administration.

[0017] Neither of the Bodor references mentions the problem ofirritation associated with the administration of these water solublecompounds or ulceration assciated with their extravasation. Furthermore,neither of the Bodor references teaches or suggests that water solublecytotoxic or antineoplastic drugs or the water-soluble salts of suchdrugs when administered with cyclodextrin compounds can significantlydecrease ulceration or irritation associated with administration orextravasation of such drugs.

[0018] Significantly the Bodor references attribute the preciptiationand organ deposition problems associated with parenteral administrationof lipophillic drugs to the effects of organic solvents used tosolubilized the drug in the parenteral vehicle. The Bodor referencesadditionally state that drugs which are particularly useful in theparenteral composition and methods disclosed therein are those which arerelatively insoluble in water but whose water solubility can besubstantially improved by formulation with 20 to 50% of the selectedcyclodextrin, e.g. HPCD, in water.

[0019] Thus it is quite clear that the Bodor references are directed toprevention of the phenomenon of precipitation of insoluble drugs andinsoluble drug-carrier complexes. There is no disclosure concerning theprevention of ulceration or irritation or of amounts of the amorphouscyclodextrin useful for the prevention of these two side effects.

SUMMARY AND OBJECTS OF THE INVENTION

[0020] The present invention provides a composition of matter comprisingan anti-ulcerationeffective amount or an anti-irritation-effectiveamount of an amorphous complex of cyclodextrin and any compound whichcan cause extravasation-associated ulceration or irritation wheninjected. In general such compounds are cytotoxic compounds, but thecompositions of matter according to the invention are not limited tocytotoxic compounds. For example certain sedative compounds wheninjected intravascularly (IV) can cause severe ulceration ifextravasation occurs. Such sedative compounds include but are notlimited to diazepam compounds including diazepam. In addition certainionotrophic drugs such as dopamine, may lead to ulceration ifextravasated or to vascular irritation when injected.

[0021] The present invention is useful in the prevention ofextravasation-associated ulceration and irritiation associated withinjection of drugs that are insoluble in water as well as drugs that aresoluble in water. It is particularly and unexpectedly effective inprevention of these side effects in the administration of water solublecytotoxic agents. In particular, the present invention is a compositionof matter that marks an improvement in the formulation of cytotoxicagents which are water soluble whereby the tendency of these agents tocause irritation or ulceration when extravasated on injection issubstantially eliminated. By combining such water soluble cytotoxicagents with a cyclodextrin compound and preferably an amorphouscyclodextrin such as an alkyl-substituted or hydroxyalkyl-substitutedα-, β-, or γ-cyclodextrin compound, irritation or ulceration whenextravasated is substantially eliminated. Applicant has furtherdiscovered that surprisingly the inclusion of an excipient such asmannitol, sorbitol or lactose further improves the performance of thecomposition in that the reduction in ulceration is even more pronouncedthan when the drug is used with the cyclodextrin compound alone.

[0022] The phenomena of ulceration and irritation should be understoodto be a different side effect than the phenomenon of precipitation whichis addressed in the Bodor references. The distinction is clearest in thecase of cytotoxic agents and particularly in the case of water solublecytotoxic agents. In general the lipophilic drugs and drug-carriercomplexes that Bodor discloses precipitate at the injection site or nearto the side of injection, even when they are properly injectedintravenously and not extravasated. Thus the fundamental teaching of theBodor references relates to solubilization of insoluble drugs so thatthey do not precipitate from the blood stream of a patient into theblood vessels near the site of injection or in more remote capillarybeds of distant organs such as the lung.

[0023] By contrast the phenomenon of extravasation occurs when the drugeither leaks from a blood vessel into the perivascular tissue or isinadvertently injected into the perivascular tissue. When certain drugsare extravasated they cause ulceration. It will therefor be appreciatedthat extravasation is particularly threatening when the drug is awater-soluble cytotoxic compound. Such water soluble drugs, instead ofprecipitating and leading to a localized ulceration, tend to disseminateinto more distant tissues from the perivascular tissue immediate to thesite of injection . This dissemination leads to extensive ulceration andnot localized precipitation. Thus for example there are many reportedcases in which localized extravasation of the water soluble agentdoxorubicin leads to disseminated ulceration of the whole limb of thepatient.

[0024] Compositions of matter according to the invention comprising anamorphous complex of cyclodextrin and a cytotoxic compound may comprisea variety of different cytotoxic compounds used for a variety oftherapeutic purposes. Such compositions according to the inventioninclude an amorphous complex of cyclodextrin and an anti-cancer,anti-neoplastic, anti-fungal antibiotic, anti-bacterial antibiotic orchemical compound. Especially preferred in the compositions according tothe invention are those in which the cytotoxic compound is one that issoluble in aqueous solution. Compounds that are soluble in aqueoussolution include those in which the active drug is soluble. Alsoincluded are those drugs in which the acid complex of the activecompound is soluble in water, such as doxorubicin hydrochloride.Additionally, a salt of an active drug formed to render the drug solubleis included in compounds that are soluble in aqueous. solution. Examplesof the latter include vincristine sulfate and vinblastine sulfate (thesulfate salts of the active drug) and erythromycin lactobionate(prepared from erythromycin base and lactobiono-δ-lactone).

[0025] The cytotoxic compound may be a synthetic chemical compound sucha nitrogen mustard derivative such as mechlorethamine. The cytotoxiccompound may be a plant alkaloid such as vincristine and vinblastine oran alkylating agent such as dacarbazine and streptozocin. The compoundmay be microbially produced and subsequently purified or partiallypurified antibiotic. Cytotoxic antibiotics that may be part of thecomposition according to the invention include those administered asanti-cancer agents, such as the mitomycins including but not limited tomitomycin-c, the bleomycins including but not limited to mixturespredominating in bleomycin A2 and B, daunorubicin, doxorubicin,idarubicin plicamycin and dactinomycin. With respect to the compositionsof matter comprising an amorphous complex of cyclodextrin and a cytoxiccompound which is a chemotherapeutic anticancer agent, the anticanceragent may be a vessicant or an irritant. Composititons of matter inwhich the anti-cancer agent is a protein biological response modifiersuch as interleukin-2 or Tumor necrosis factor are not intended as theanti-cancer agents of the composition according to the invention;however compositions of matter which include such protein biologicaalresponse modifiers and an anti-neoplastic chemotherapeutic agent areintended as compositions according to the invention.

[0026] Other cytotoxic antibiotics that may be part of the compositionaccording to the invention include antifungal antibiotic agents such asamphoteracin B and certain anti-bacterial antibiotics, such astetracycline and erythromycin that may lead to ulceration ifextravasated or to vascular irritation when injected. Additionally, thecompositions according to the invention include pharmaceutical compoundswhich are not administered to achieve a specific cytotoxic effect, butwhich may also result in extravasation-associated ulceration. Suchcompounds which may be part of the compositions according to theinvention include, for example certain sedative compounds typified bybenzodiazapine compounds including but not limited to diazepam.

[0027] The compositions of matter according to the invention may alsoinclude, in addition to the amorphous complex of cyclodextrin andcytotoxic compound, carriers, bulking agents and other pharmaceuticallyacceptable excipients such as mannitol, sorbitol, lactose, dextrox andthe like. Surprisingly, it has been found that certain chemotherapeuticcompounds and such excipients, particularly mannitol, when formulatedwith cyclodextrin do not cause any significant extravasation whenadministered to mammalian subjects.

[0028] The composition of matter according to the invention may besupplied as a dry powder or as a solution. If the composition of matteris to be injected into a subject it will be rendered sterile prior toinjection. Accordingly, the composition of matter according to theinvention may be supplied as a sterile cake, plug or powder or as asterile lyophilized preparation in a sterile vial suitable for theaddition of a sterile diluent, or as a sterile liquid solution in asterile container.

[0029] It is an object of the present invention to provide compositionsof matter which substantially reduce ulcerationassociated withextravasation caused by compounds which can cause such ulcerationcomprising an amorphous complex of cyclodextrin and such compound.

[0030] Another object othe present invention to provide compositions ofmatter which substantially reduce ulceration associated withextravasation caused by compounds that are soluble in aqueous solutionwhich can cause such ulceration comprising an amorphous complex ofcyclodextrin and such compound that is soluble in aqueous solution.

[0031] It is a further object of the present invention to providecompositions of matter which substantially reduce ulceration associatedwith extravasation caused by cytotoxic drugs which can cause suchulceration comprising an amorphous complex of cyclodextrin and acytotoxic drug.

[0032] It is another object to the invention to provide compositions ofmatter which substantially reduce ulceration associated withextravasation caused by antibiotics which can cause such ulcerationcomprising an amorphous complex of cyclodextrin and such an antibiotic.

[0033] It is yet another object to the invention to provide compositionsof matter which substantially reduce ulceration associated withextravasation caused by antineoplastic drugs which can cause suchulceration comprising an amorphous complex of cyclodextrin and suchantineoplastic drugs.

[0034] It is an object of the present invention to provide compositionsof matter which substantially reduce ulceration associated withextravasation caused by compounds which can cause such ulcerationcomprising an ulceration reducing amount of an amorphous complex ofcyclodextrin and such compound.

[0035] Another object othe present invention to provide compositions ofmatter which substantially reduce ulceration associated withextravasation caused by compounds that are soluble in aqueous solutionwhich can cause such ulceration comprising an ulceration-reducing amountof anamorphous complex of cyclodextrin and such compound that is solublein aqueous solution.

[0036] It is a further object of the present invention to providecompositions of matter which substantially reduce ulceration associatedwith extravasation caused by cytotoxic drugs which can cause suchulceration comprising an ulceration-reducing amount of an amorphouscomplex of cyclodextrin and a cytotoxic drug.

[0037] It is another object to the invention to provide compositions ofmatter which substantially reduce ulceration associated withextravasation caused by antibiotics which can cause such ulcerationcomprising an ulceration-reducing amount of an amorphous complex ofcyclodextrin and such an antibiotic.

[0038] It is yet another object to the invention to provide compositionsof matter which substantially reduce ulceration associated withextravasation caused by antineoplastic drugs which can cause suchulceration comprising an ulceration-reducing amount of an amorphouscomplex of cyclodextrin and such an antineoplastic agent.

[0039] Still another object of the invention is to provide a method forreducing the likelihood of ulceration in subjects in need of parenteraltreatment with compounds that if extravasated have the potential forcausing ulceration, comprising administering to such subjects apreparation comprising at least one compound that if extravasated hasthe potential for causing ulceration and an anti-ulceration-effectiveamount of cyclodextrin or amorphous cyclodextrin.

[0040] Yet still another object of the invention is to provide a methodfor reducing the likelihood of irritation in subjects in need ofparenteral treatment with compounds that when administered parenterally,particularly intravenously, have the potential for causing irritation,comprising administering to such subject a preparation comprising atleast one compound that has the potential for causing irritation and ananti-irritation-effective amount of cyclodextrin or amorphouscyclodextrin.

DETAILED DESCRIPTION OF THE INVENTION

[0041] By cyclodextrin is meant α-, β-, or γ-cyclodextrin. Cyclodextrinsare described in detail in Pitha et al., U.S. Pat. No. 4,727,064 whichis incorporated herein by reference. Cyclodextrins are cyclic oligomersof glucose; these compounds form inclusion complexes with any drug whosemolecule can fit into the lipophile-seeking cavities of the cyclodextrinmolecule.

[0042] By amorphous cyclodextrin is meant non-crystalline mixtures ofcyclodextrins wherein the mixture is prepared from α-, β-, orγ-cyclodextrin . In general the amorphous cyclodextrin is prepared bynon-selective additions, expecially alkylation of the desiredcyclodextrin species. Reactions are carried out to yield mixturescontaining a plurality of components thereby preventing crystallizationof the cyclodextrin. various alkylated and hydroxyalkyl-cyclodextrinscan be made and of course will vary, depending upon the starting speciesof cyclodextrin and the addition agent used. Among the amorphouscyclodextrins suitable for compositions according to the invention arehydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotrosylderivatives of β-cyclodextrin, carboxyamidomethyl-β-cyclodextrin,carboxymethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin anddiethylamino-β-cyclodextrin. In the compositions according to theinvention hydroxy-β-cyclodextrin is preferred. The substitutedγ-cyclodextrins may alsobe uirable, including hydroxyproply,hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives ofγ-cyclodextrin.

[0043] By cyclodextrin compound is meant cyclodextrin and amorhpouscyclodextrin.

[0044] The term “pharmaceutically accepted or acceptable excipient”means an ingredient used in a pharmaceutical preparation which doesfunction as an active agent. Such pharmaceutically acceptable excipientsare used for various purposes, such as stabilizers, buffers, suspendingagents, carriers and the like and are listed and described in a numberof texts including for example, the British Pharmacopeia, the JapanesePharmacopeia and the United States Pharmacopeia XXII and NationalFormulary XVII and supplements thereto. Suitable excipients forinjectable pharmaceutical compositions are typified by non-reducingsugars or sugar alcohols such as mannitol and sorbitol. Glucose, andlactose may also be used as excipients.

[0045] By dactinomycin (actinomycin-D) is meant an antibiotic substancebelonging to the actinomycin complex produce by several Streptomycesspecies having the elemental composition of C₆₂H₈₆N₁₂O₁₆, and molecularweight 1255.47 . It is sold under the trade name Cosmegen (Merck, Sharp& Dohme) as a sterile lyophilized powder including dactinomycin andmannitol.

[0046] By mithramycin is meant an antibiotic substance identified asaurelic acid, produce by several Streptomyces species includingStreptomyces argillaceus and Streptomyces tanashiensis, having theelemental composition of C₅₂H₇₂O₂₄, chemical formula[2S-{2∝,3β(1R*.3R*.4S*)]]-6-{(2,6-Dideoxy-3-O-(2,6-dideoxy-β-D-arabino-hexopyranosyl-β-D-arabino-hexopyranosyl]oxy]-2-[O-2,6-dideoxy-3-C-methyl-β-D-ribo-hexopyranosyl-(1-4)-O-2,6-dideoxy-∝-D-lyxo-hexopyranosyl-(1-3)-2,6-dideoxy-β-D-arabino-hexopyranosyl)oxy]-3-(3,4dihydrox-1-methyl-2oxopentyl)-3,4-dihydro-8,9-dihydroxy-7-methyl-1(2H)-anthracenonemolecular weight 1085.18. It is also know under the generic nameplicamycin. It is sold under the trade name Mithracin (Miles, Inc.Pharmaceutical Division) as a sterile freeze dried preparation forintravenous administration including mithramycin and mannitol andsufficient disodium phosphate to adjust to pH 7.

[0047] By mitomycin-C is meant one of a group of anti-neoplasticantibiotics substances mitomycin-A, -B, and -C produced by Streptomycescaespitosus (griseovanaceseus). Mitomycin-D has also been isolated fromStreptomyces verticillatus. Mitomycin-C has the elemental composition ofC₁₅H₁₈N₄O₆ and chemical formula[1aR]-6-amino-8-[[aminocarbonyl)oxy]methyl]-1,1a,2,8,8a,8b-hexahydro-8a-methoxy-5-methylazirinol[2′,3′:3,4]pyrrolo[1,2-a]indole-4,7-dione.It is sold under the trade name Mutamycin (Bristol-Myers OncologyDivision, Bristol-Myers Squibb Company) as a sterile powder includingmannitol.

[0048] By N-methyl mitomycin-C is meant an anti-bacterialanti-neoplastic substance, also called porfiromycin, isolated from aStreptomyces ardus fermentation broth and also isolated fromStreptomyces verticillatus. N-methyl mitomycin-C has the elementalcomposition of C₁₆H₂₀N₄O₅ and chemical formula6-amino-8-[[aminocarbonyl)oxy]methyl]-1,1a,2,8,8a,8b-hexahydro-8a-methoxy-1,5-dimethylazirinol[2′,3′:3,4]pyrrolo[1,2-a]indole-4,7-dione.

[0049] By alkaloid is meant an amine containing compound originallyisolated from a plant which may be commercially produced by extractionfrom plant material and purification, or by synthetic or semi-syntheticmeans.

[0050] By vincaalkaloid is meant alkaloid compounds originally isolatedform the plant Vinca rosea Linn (Catharanthus roseus or Apocynaceae),and Vinca minor. These compounds are useful in several therapeuticcategories including anti-neoplastics and vasodialators. Among thesecompounds are vinblastine, vincamine, vincine, vincaminine, vincinine,vincristine and the synthetic dimer of vinblastine, vindesine.

[0051] By vincristine is meant a vincaalkaloid identified as22-Oxoyincaleukoblastine or leurocristine acid, originally isolated fromthe plant Vinca rosea Linn, having the elemental composition ofC₄₆H₅₆N₄O₁₀, and molecular weight 824.94, and its sulfate salt havingthe elemental composition C₄₆H₅₆N₄O₁₄S and molecular weight 923.04. Thesulfate salt of vincristine is sold under the trade name Oncovin (EliLilly and Company) as a sterile liquid containing vincristine, mannitol,methylparaben, propylparaben and water with acetic acid and sodiumacetate added for pH control.

[0052] By vinblastine is meant a vincaalkaloid identified asVincaleukoblastine, originally isolated from the plant Vinca rosea Linn,having the elemental composition of C₄₆H₅₆N₄O₉, and molecular weight811.00, and its sulfate salt having the elemental compositionC₄₆H₆₀N₄O₁₃S and molecular weight 909.10. The sulfate salt ofvinblastine is sold under the trade name Velban (Eli Lilly and Company)as a sterile lyophilized plug containing no excipients.

[0053] By “anti-ulceration-effective amount” means an amount of asubstance which when combined with a compound, cytotoxic drug,antibiotic or alkaloid, with or without an excipient and administered toa subject, significantly reduces the extent of ulceration that occurs,if any, compared to the extent of ulceration caused by the same amountof compound, cytotoxic drug, antibiotic or alkaloid, with or without anexcipient when administered alone to a subject. Included in thephenomena defined herein as ulceration or ulcer are those phenomenausually associated with vesicants. See, Chapter 8 “Extravasation” inCancer Chemotherapy, A Reference Guide, Linda Tenenbaum, W.B. SaundersCompany, Harcourt Brace Jovanovich, Inc Philadelphia (1989); and Chapter5 “Common Toxicities” in Cancer Chemotherapy Handbook, Robert T. Dorrand William L. Fritz, Elsevier, N.Y. The term ulceration or ulcer is notintended to include gastrointestinal, duodenal or intestinal irritationor ulceration associated with the oral administration of a number oforal analgesic and anti-inflammatory drugs such as indomethacin

[0054] By vesicant is meant a chemotherapeutic agent which is topicallytoxic. If inadvertantly delivered outside of a vein, a vesicant has thepotential to cause pain, cellular damage including cellulitis, tissuedestruction (necrosis) with formation of a sore or ulcer and sloughingof tissues that may be extensive and require skin grafting. Examples ofanti-cancer chemotherapeutic agents that are vesicants include but arenot limited to Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin,Idarubicin, Mechlorethamine, Mitomycin C, Vinblastine, Vincristine andVindesine.

[0055] By anti-irritation-effective amount means an amount of asubstance which when combined with a compound, cytotoxic drug,antibiotic or alkaloid, with or without an excipient and administered toa subject, significantly reduces the extent of irritation that occurs,if any, compared to the extent of irritation caused by the same amountof compound, cytotoxic drug, antibiotic or alkaloid, with or without anexcipient when administered alone to a subject. Included in thephenomena defined herein as irritation are those phenomena usuallyassociated with irritants. See, Chapter 8 “Extravasation” in CancerChemotherapy, A Reference Guide, Linda Tenenbaum, W.B. Saunders Company,Harcourt Brace Jovanovich, Inc Philadelphia (1989) and Chapter 5 “CommonToxicities” in Cancer Chemotherapy Handbook, Robert T. Dorr and WilliamL. Fritz, Elsevier, N.Y. The term irritation is not intended to includegastrointestinal, duodenal or intestinal irritation or ulcerationassociated with the oral administration of a number of oral analgesicand anti-inflammatory drugs such as indomethacin.

[0056] By irritant is meant a chemotherapeutic agent that may producepain and inflammation at the administration site or along the path ofthe vein (phlebitis) by which it is administered. Examples ofanti-cancer chemotherapeutic agents which are irritants include but arenot limited to Carmustine, Dacarbazine, Etoposide, Plicamycin,Etoposice, Streptozocin and Tenoposide.

[0057] By aqueous solution is meant solutions comprised of at least 90%water (weight/volume).

[0058] By cytotoxic is meant having the property of killing cells at lowmolar concentrations.

[0059] By antibiotic is meant compounds produced by microorganisms, andderivatives of such. compounds, which are capable at concentrationsabove a particular threshold concentration of killing othermicroorganisms and/or cells including mammalian cells.

[0060] By anti-cancer antibiotic is meant an antibiotic which is capableof killing cancerous cells.

[0061] By aminoglycoside antibiotic is meant an antibiotic compoundcontaining nitrogen, usually in the form of at least one amino groupwherein the compound also contains at least one glycoside bond to asugar or saccharide moiety.

[0062] By daunorubicin is meant an antibiotic of the rhodomycin group,originally isolated from fermentation broths of Streptomyces peuicetiusor Streptomyces coentleonibidus and its acid complexes particularly itshydrochloride complex. Daunorubicin is a glycoside formed by atetracyclic aglycone daunomycinone and an amino sugar daunosamine.Daunorubicin has the elemental composition of C₂₇H₂₉NO₁₀ and chemicalformula8-Acetyl-10-[3-amino-2,3,6-tri-deoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,-l11-trihydroxy-1-methoxy-5,12-naphthacenedione, and molecular weight527.51. Daunorubicin is sold under the trade name Cerubidine (WyethAyerst Laboratories) as a sterile lyophilized powder with mannitol.

[0063] By doxorubicin is meant 14-hydroxydaunomycin a derivative ofdaunorubicin, and its acid complexes particularly its hydrochloridecomplex) having the elemental composition C₂₇H₂₉NO₁₁ and chemicalformula 10-[(3-amino-2,3,6-tri-deoxy-α-L-lyxo-hexopyransoyl)oxy]-7,8,9,10-tetrahydro-6,8,-11-trihydroxy-8-(hydroxyacetyl)- 1methyoxy-5,12-naphthacenedione andmolecular weight 543.54. Doxorubicin HCL is sold as a generic drug byvarious manufacturers as a sterile lyophilized powder with mannitol andas a sterile solution of doxorubicin hydrochloride in sterile water forinjection made iso-osmotic with sodium chloride and dextrose or othersuitable added excipient.

[0064] By bleomycins is meant a group of related glycopeptide antibioticsubstances including bleomycin-A, -B and -C and their components.Bleomycins are isolated from Streptomyces verticillatus. The bleomycinsdiffer from one another in their terminal amines and show varyingbiological activity. Bleomycin A₂ is the main component of the bleomycinemployed clinically as an anti-cancer antibiotic. Bleomycin-A₂ has theelemental composition of C₅₅H₈₄N₁₇O₂₁S₃ and chemical formulaN¹-[3-(dimethylsulfonio)-propyl]bleomycinamide. Also included in thisdefinition are the sulfate salts of the bleomycins.

[0065] By bleomycin is meant a mixture of basic cytotoxic glycopeptidesproduced by the growth of Streptomyces verticillatus or by other meansand the sulfate salts thereof. In general HPLC analysis of bleomycinaccording to the definition shows the following contents, in order ofelution as described in United States Pharmacopeia XXII: bleomycinicacid, bleomycin A2, bleomycin A5, bleomycin B2 and bleomycin B4. In apreferred embodiment of the invention Bleomycin as used herein conformsto the description of Bleomycin Sulfate in the United StatesPharmacopeia XXII in that the content of the sulfate salts of bleomycinA2 is between 55% and 70%, bleomycin B2 is between 25% and 32% andbleomycin B4 is not more than 1%; and the combined percentage of thesulfate salts of bleomycins A2 and B2 is not less than 85%. A mixture ofbleomycin A2 and bleomycin B2 (or their sulfate salts), wherein theconcentration of bleomycin B2 is no less than 25% is also within thepresent definition of bleomycin. Bleomycin is sold under the trade nameBlenoxane (Bristol-Myers Oncology Division, Bristol-Myers SquibbCompany) as a sterile powder including mannitol.

[0066] By diazepam is meant is meant a benzodiazepine derivative havingthe chemical formula7-chloro-1,3(dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one andhaving a molecular weight of 284.7. Diazepam is sold under the tradenameValium (Roche Products, Inc.) and includes diazepam compounded withpropylene glycol, ethyl alcohol, sodium benzoate and benzoic acid andbenzyl alcohol.

[0067] Cytotoxic agents that are soluble in aqueous solution include butare not limited to antineoplastic compounds chosen from the followingTable A. The solubilities of the compounds listed in Table A arecompiled from a number of references including The Merck Index 10thEdition, the Physicians Desk Reference (1992 edition) , and TheCytotoxics Handbook (Radcliff Medical Press, Oxford 1993) which areincorporated herein by reference. TABLE A Anti-cancer Agents Soluble inAqueous Solution Name of Drug Solubility Reference dactinomycin solublein water-glycol MI* dacarbazine soluble in 10% citric acid water CTX**daunorubicin soluble in water Ml doxorubicin soluble in water MIvincristine sulphate soluble in water (50% solution) CTX vinblastinesulphate soluble in water (10% solution) CTX mithramycin soluble inwater CTX streptozocin soluble in water CTX mitomycin C soluble in waterMI bleomycin soluble in water CTX

[0068] Bearing in mind the above described definitions, the presentinvention is for novel compositions of matter comprising an ulceration-reducing or irritation-reducing amount of a cyclodextrin compound and acytotoxic compound. In a preferred embodiment the cyclodextrin is asubstituted amorphous cyclodextrin, such as an alkyl or hydroxy alkylsubstituted, including hydroxypropyl, hydroxyethyl, glucosyl, maltosyland maltotrosyl derivatives of β-cyclodextrin or γ-cyclodextrin and thecytotoxic agent is one that is soluble in aqueous solution.

[0069] In general, the invention provides a composition of mattercomprising an amorphous complex of cyclodextrin and any compound whichcan cause extravasation-associated ulceration or irritation wheninjected. While many such compounds are cytotoxic compounds, thecompositions of matter according to the invention are not limited tocytotoxic compounds. For example certain sedative compounds wheninjected intravascualrly (iv) can cause severe ulceration ifextravasation occurs. Such sedative compounds include but are notlimited to diazepam compounds including diazepam.

[0070] Compositions of matter comprising an amorphous complex ofcyclodextrin and a cytotoxic compound according to the invention maycomprise a variety of different cytotoxic compounds used for a varietyof therapeutic purposes. Such compositions according to the inventioninclude an amorphous complex of cyclodextrin and an anti-cancer,anti-neoplastic, anti-fungal antibiotic, anti-bacterial antibiotic orchemical compound.

[0071] With respect to the compositions of matter comprising anamorphous complex of cyclodextrin and a cytotoxic compound which is achemotherapeutic anticancer agent, the anticancer agent may beclassified as a vesicant or an irritant. Examples of anti-cancerchemotherapeutic agents that are vesicants include but are not limitedto Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin,Mechlorethamine, Mitomycin C, Vinblastine, Vincristine and Vindesine.Examples of anti-cancer chemotherapeutic agents which are irritantsinclude but are not limited to Carmustine, Dacarbazine, Etoposide,Plicamycin, Etoposide, Streptozocin and Tenoposide.

[0072] The effects of such agents on patients are found in the followingTable B: TABLE B Acute Local tissue Drug Frequency of Phlebitis Effects(infiltration) Anthracyclines Daunorubicin Frequent Tissue sloughDoxorubicin Frequent Large, spreading Dactinomycin Frequent ulcerations;deep tissues Idarubicin Frequent affected Alkaloids VincristineInfrequent Vinblastine Frequent Cellulitis if small dose TenoposideFrequent Slough if large dose Nitrosoureas Streptozotocin InfrequentExtravasation can cause Carmustine Infrequent extreme pain and necrosisOthers Mitomycin Frequent Pain and eventual tissue sloughing MithramycinInfrequent Chromomycin A₃ Frequent Sever tissue sloughing DecarbazineFrequent Pain, mild inflammation, slight necrosis

[0073] In general, the composition of matter according to the inventionwill comprise a sufficient amount of the compound to exert its desiredpharmacological effect when administered IV, whether it is for examplesedation, anti-fungal activity, anti-neoplastic activity, and an amountof cyclodextrin compound sufficient to significantly reduce the extentof ulceration or irritation that would occur if a like amount of thecompound were extravasated or administered IV without extravasation inthe absence of the cyclodextrin compound. If the anticancer compound isa vesicant the composition of matter according to the invention willcomprise a sufficient amount of the anticancer compound to exert itsdesired cytotoxic effect against targeted cancer cells and ananti-ulceration-effective amount of cyclodextrin, with or without anexcipient. Likewise, if the anticancer compound is an irritant, thecomposition of matter according to the invention will comprise asufficient amount of the anticancer compound to exert its desiredcytotoxic effect against target cancer cells andanti-irritation-effective amount of cyclodextrin with or without anexcipient.

[0074] The anti-cancer chemotherapeutic compounds that may comprise thecomposition according to the invention will be any anticancerchemotherapeutic compound that causes irritation, as defined herein, orulceration, as defined herein, upon extravasation. The compound may be asynthetic chemical compound such a nitrogen mustard derivative forexample mechlorethamine. The antineoplastic compound may be a plantalkaloid. With respect to such plant alkaloids, taxol, a chemicalcompound derived from the bark of the Pacific Yew tree, andpharmacologically active related compounds are contemplated. Alsocontemplated are water soluble compounds related to taxol such astaxotrere. While taxol is not water soluble, ulcerative activity causedby this anti-neoplastic compound may be significantly reduced byadministration with hydroxypropyl-β-cyclodextrin and it is believed thatfurther improvement in anti-ulcerativie effect will be obtained withamorphous γ-cyclodextrins Also contemplated in the compositionsaccording to the invention are the vinca alkaloids. Such vinca alkaloidsas vincristine and vinblastine and vindisine are particularly strongvesicants.

[0075] Also among the anti-cancer chemotherapeutic compounds that maycomprise the composition according to the invention are alkylatingagents which are used as anti-cancer chemotherapeutics such asdacarbazine and streptozocin.

[0076] The composition according to the invention may comprise a complexof cyclodextrin and a microbial produced antibiotic compound which issubsequently purified or partially purified. Cytotoxic antibiotics thatmay be part of the composition according to the invention include thoseadministered as anti-cancer agents, such as the mitomycin including butnot limited to mitomycin-c, the bleomycins including but not limited tomixtures predominating in bleomycin A2 and B, daunorubicin, doxorubicin,plicamycin and dactinomycin. All of the forgoing are soluble in aqueoussolution.

[0077] Anti-cancer agents which are protein biological response modifiersuch as interleukin-2 or Tumor Necrosis Factor are not intended as theanti-cancer agents of the compositions according to the invention sincethey do not cause ulceration or irritation as defined herein resultingfrom extravasation ; however compositions of matter which include suchprotein biological response modifiers and an anti-neoplasticchemotherapeutic agent which does cause extravasation associatedirritation or ulceration are intended as compositions according to theinvention.

[0078] The composition according to the invention may comprise a complexof cyclodextrin and other cytotoxic anti-fungal antibiotic agents suchas amphoteracin B.

[0079] Additionally, the compositions according to the invention includepharmaceutical compounds which are not administered to achieve aspecific cytotoxic effect, but which may also result inextravasation-associated ulceration. Such compounds which may be part ofthe compositions including cyclodextrin according to the inventioninclude, for example certain sedative compounds typified bybenzodiazapine compounds including but not limited to diazepam. In thisinstance, the composition according to the invention comprises an amountof the compound sufficient to exert the desired pharmacological effectwhen administered iv and an anti-ulceration or anti-irritation effectiveamount of the cyclodextrin compound.

[0080] The compositions of matter according to the invention may alsoinclude, in addition to the complex of cyclodextrin and achemotherapeutic compound , carriers, bulking agents and otherpharmaceutically acceptable excipients such as mannitol, sorbitol,lactose, sucrose and the like. Surprisingly, it has been found thatchemotherapeutic compounds and such excipients, particularly mannitol,when formulated with cyclodextrin do not cause any significantulceration if extravasated when administered to mammalian subjects.

[0081] The cyclodextrin of the compositions according to the inventionmay be α, β, or γ-cyclodexrin. α-cyclodextrin contains six glucopyranoseunits; β-cyclodextrin contains seven glucopyranose units; andγ-cyclodextrin contains eight glucopyranose units. The molecule isbelieved to form a truncated cone having a core opening of 4.7-5.3 Å,6.0-6.5 Å and 7.5-8.3 Å in α-, β-, or γ-cyclodextrin respectively. Thecomposition according to the invention may comprise a mixture of two ormore of the α-, β-, or γ-cyclodextrins. Usually, however the compositionaccording to the invention will comprise only one of the α-, β-, orγ-cyclodextrins. The particular α-, β-, or γ-cyclodextrin to be usedwith the particular cytotoxic compound to form the compositionsaccording to the invention may be selected based on the known size ofthe molecule of the cytotoxic compound and the relative size of thecavity of the cyclodextrin compound. Generally if the molecule of thecytotoxic compound is relatively large, a cyclodextrin having a largercavity is used to make the composition according to the invention.Furthermore, if the cytotoxic compound is administered with an excipientit may be desirable to use a cyclodextrin compound having a largercavity in the composition according to the invention.

[0082] The unmodified α-, β-, or γ-cyclodextrins are less preferred inthe compositions according to the invention because the unmodified formstend to crystalize and are relatively less soluble in aqueous solutions.More preferred for the compositions according to the invention are theα-, β-, and γ-cyclodextrins that are chemically modified or substituted.Chemical substitution at the 2,3 and 6 hydroxyl groups of theglucopyranose units of the cyclodextrin rings yields increases insolubility of the cyclodextrin compound.

[0083] Most preferred cyclodextrins in the compositions according to theinvention are amorphous cyclodextrin compounds. By amorphouscyclodextrin is meant non-crystalline mixtures of cyclodextrins whereinthe mixture is prepared from α-, β-, or γ-cyclodextrin. In general, theamorphous cyclodextrin is prepared by non-selective alkylation of thedesired cyclodextrin species. Suitable alkylation agents for thispurpose include but are not limited to propylene oxide, glycidol,iodoactamide, chloroacetate, and 2-diethylaminoethlychloride. Reactionsare carried out to yield mixtures containing a plurality of componentsthereby preventing crystallization of the cyclodextrin. variousalkylated cyclodextrins can be made and of course will vary, dependingupon the starting species of cyclodextrin and the alkylating agent used.Among the amorphous cyclodextrins suitable for compositions according tothe invention are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl andmaltotrosyl derivatives of β-cyclodextrin,carboxyamidomethyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin,hydroxypropyl-β-cyclodextrin and diethylamino-β-cyclodextrin . In thecompositions according to the invention hydroxypropyl-β-cyclodextrin ispreferred although the α- or γ-analogs may also be suitable. Theparticular alkylated α-, β-, or γ-cyclodextrin to be used with theparticular cytotoxic compound to form the compositions according to theinvention will be selected based on the size of the molecule of thecytotoxic compound and the relative size of the cavity of thecyclodextrin compound. As with the unsubstituted cyclodextrins mentionedabove, it may be advantageous to use alkylated cyclodextrin having alarger cavity when the composition according to the invention alsoincludes an excipient. The use of a particular α-, β-, or γ-cyclodextrinwith a particular cytotoxic compound or cytotoxic compound and excipientin the compositions according to the invention may of course beoptimized based on the effectiveness in reducing ulceration orirritation.

[0084] Another significant factor in determining the anti-ulcerative andanti irritation effects of complexes of substituted cycldextrinsandcytotoxic drugs is the degree of substitution of substituent groupsin the cyclodextrin molecule, whether it is α-, β-, or γ-cyclodextrin.By degree of substitution is meant the number of substituent moleculesper molecule of cyclodextrin. In the compostion according to theinvention a higher average degree of substitution of substuient groupsin the cyclodextrin molecule is believed to be preferable. Suchsubstitutent groups are exemplified by those mentioned in the paragraphabove. A degree of substitution in the range of about 4 to about 10 forhydroxypropyl substituents may be effective with mitomycin-c anddoxorubicin. A degree of substitution in the range of about 5 to about 9is preferred and is expected to be anti-ulcertaion effective forcompositions including both water soluble anti-neoplastic agents such asthose mentioned herein above and water insoluble antineoplastic agentssuch as taxol.

[0085] As mentioned above, the compositions of matter of the inventioncomprise a cytotoxic compound and cyclodextrin. The relative amounts ofcytotoxic compound and cyclodextrin will vary depending upon therelative toxicity of the compound and the effect of the cyclodextrin onthe compound. In general, the ratio of the weight of cytotoxic compoundto the weight of cyclodextrin compound will be in a range between 1:20and 1:5000. Within this range, the ulcerative effects of many cytotoxiccompounds will be significantly reduced when the ratio of the weight ofcytotoxic compound to the weight of cyclodextrin compound is in a rangebetween 1:50 and 1:2000. A weight to weight ratio in a range of 1:50 to1:2000 and more preferably in a range of 1:50 to 1:800 cf cytotoxicchemotherapeutic compound to cyclodextrin are believed to be effectivefor a number of vesicant anti-cancer chemotherapeutics. For exampleMitomycin in a ratio of between 1:100 to 1:300 (drug to cyclodextrin)significantly reduces the extent of ulceration clue to intradermallydeposited mitomycin C. When mitomycin C in a weigh to weight ratio withβ-hydroxypropyl cyclodextrin of 1:160 was injected intradermally in amammalian subject the lesion resulting from the injection was about onethird the size of the lesion cause by intradermal injection of the sameamount of mitomycin C without the cyclodextrin compound. Furthermorewhen mitomycin-C together with the excipient mannitol in a weight toweight ratio with β-hydroxypropyl cyclodextrin of 1:400 (mitomycin:β-hydroxypropyl cyclodextrin) was injected intradermally in a mammaliansubject, the lesion resulting from the injection was eliminated entirelyin 80% of the test subjects, and in the remaining test subjects thelesion was about one tenth the size of the lesion cause by intradermalinjection of the same amount of mitomycin C and mannitol without thecyclodextrin compound.

[0086] The compositions of matter according to the invention may bysupplied as a powder comprising the active pharmaceutical compound andcyclodextrin compound. If the composition is to be administeredparenterally, for example iv, the composition of matter will be renderedsterile prior to such administration. Any of the several known means forrendering such pharmaceutical preparations sterile may be used so longas the active pharmaceutical compound is not inactivated. If the activepharmaceutical compound is heat stable, the composition of matteraccording to the invention may be heat sterilized. If the cytotoxiccompound is not heat stable but is not photodegraded the composition maybe sterilized by exposure to ultraviolet light. Alternatively, thecomposition of matter if in a powder form may be gas sterilized usingfor example ethylene oxide gas. In another alternative, the compositionof matter according to the invention may be filter sterilized using a 2micron filter. If the composition of matter is a aqueous liquid, it maybe filled in a sterile container and supplied as a sterile liquid readyfor further dilution or injection neat Alternatively such sterileliquids may be freeze dried or lyophilized in a sterile container andcapped.

[0087] In general the compositions of matter according to the inventionwill be made by dissolving the cyclodextrin in water and adding theactive compound to the aqueous cyclodextrin solution. Excipients, if anyare desired may be added with or subsequent to adding the activecompound. The resulting solution may be sterilized using any of theknown methods appropriate to preserving the active compound.Alternatively, the components may be sterilized by any of the knownmethods appropriate to preserving the active compound prior to mixing inwater an may be mixed using sterile equipment and technique. Thesolution may be lyophilized in sterile containers and capped. Prior touse the lyophilized composition of matter may be reconstituted usingsterile water for injection.

[0088] It will be understood that the compositions of matter accordingto the invention provide novel methods of controlling and reducing theincidence of ulceration associated with extravasation and irritationassociated with intravenous administration of many pharmaceuticalcompounds. The compositions of matter according to the invention providea method for reducing the likelihood of ulceration in subjects in needof parenteral treatment with compounds that if extravasated have thepotential for causing ulceration, by administering to such subjects apreparation comprising at least one compound that if extravasated hasthe potential for causing ulceration and an anti-ulceration-effectiveamount of cyclodextrin or amorphous cyclodextrin. Furthermore, thecompositions according to the invention provide a method for reducingthe likelihood of irritation in subjects in need of parenteral treatmentwith compounds that when administered parenterally, particularlyintravenously, have the potential for causing irritation, byadministering to such subject a preparation comprising at least onecompound that has the potential for causing irritation and ananti-irritation-effective amount of cyclodextrin or amorphouscyclodextrin.

[0089] It will be understood that the present invention provides bothcompositions of matter and methods for the substantial reduction ininjuries caused as a result of extravasation. While it is heretoforeknown that compositions of amorphous cyclodextrin and compounds that arenot soluble in water because they are lipophilic have the property ofreducing precipitation of compounds at or near the injection site, theheretofore known compositions and methods fail to make any observationon the effect of extravasated compounds, or the amounts of amorphouscyclodextrin needed to prevent the ulcerative effects of suchextravasated compounds.

[0090] Accordingly, the present invention is directed to compositionscomprising anti ulceration-effective amounts of amorphous cyclodextrinand compounds that otherwise cause ulceration when extravasated. Suchcompounds may be soluble in aqueous solution or alternatively may belipophilic and as a result tend to precipitate in aqueous solutions.Since amorphous cyclodextrins are taught in the art to solubilizecompounds that are not soluble in water, it is surprising, andheretofore unobserved and unreported that compositions of mattercomprising amorphous cyclodextrin and such insoluble compounds, whichhave been rendered soluble by complexation with cyclodextrin do not leadto ulceration when extravasated. This observation is especiallysurprising because water soluble cytotoxic compounds frequently causeulceration when extravasated, and it would be expected that lipophiliccytotoxic compounds rendered soluble by complexation with cyclodextrinwould similarly remain cytotoxic.

[0091] Even more unexpected is the effect of forming complexes withcyclodextrin compounds on ulceration associated with extravasation usingcytotoxic compounds that are soluble in aqueous solution and which arenot expected to precipitate at or near the site of injection. Indeed,the literature on extravasation toxicity indicates that the problem oftoxicity associated with extravasation of water soluble compounds isexacerbated by the solubility of these compounds. Such water solubletoxic compounds rather than precipitating appear to spread throughoutthe limb when extravasated. It is thus unexpected that the ulcerativetoxicity of such compounds would be curtailed by complexation with acyclodextrin compound or that complexation of such compounds that aresoluble in aqueous solution with a cyclodextrin compound would occur atall.

[0092] The invention will be better understood from the followingexamples which are intended to be merely illustrative of the inventionand are not intended to be limiting.

EXAMPLE I Effects of Hydroxypropylcyclodextrin (HPCD) on Mitomycin-cSolubility

[0093] Purified mitomycin C was divided into aliquot ranging from 0 to10 mg and were place in pre-weighed 12×75 mm glass tubes. To each tubewas added 1 ml of double distilled water, 20% HPCD ( weight/volume (w/v)in double distilled water) or 40% HPCD w/v. HPCD had a degree ofsubstitution of 7. Each tube was vortexed for 1 minute and allowed tostand at room temperature for 1 hour at which time they were revortexedfor 1 minute. Tubes were then centrifuged for 4 minutes in a Triaccentrifuge to concentrate the undissolved mitomycin-c in the bottom ofthe tube. The dissolved mitomycin, along with the diluent was decanted.The tubes containing the undissolved mitomycin-c were dried at 80° C.and reweighed to determine the weight of insoluble mitomycin-c. Theresults are shown in Table I. TABLE I % HPβCD dose mitomycin-c (mg) mginsoluble % solubility (H₂O) 0 0 — 1 0 100 2.5 0 100 5 2.7 46 10 6.0 4020% 0 0 1 0 100 2.5 0 100 5 0 100 10 4.7 53 40% 0 0 1 0 100 2.5 0 100 50 100 10 1.1 89

[0094] In water, mitomycin-c was completely soluble up to aconcentration of 2.5 mg/ml, but solubility was limited to 46% and 40% atthe 5 and 10 mg/ml concentrations, respectively. Hence in water thelimits of solubility of mitomycin-c appeared to be about 2.5 mg/ml.Solubility of mitomycin-c was improved in HPCD. In 20% HPCD mitomycin-cwas completely soluble at 5 mg/ml and 50% soluble at 10 mg/ml,indicating that the solubility limits in 20% HPCD was about 5 mg/ml. In40% HPC, mitomycin-C was completely soluble through 5 mg/ml. These dataindicate that 40% HPCD increased mitomycin-c solubility by 3- to 4-fold.

EXAMPLE II Effects of HPCD on Mitomycin-c Extravasation Toxicity

[0095] Based upon the solubility study of Example I and a preliminaryanimal evaluation to optimize lesion size, 1.25 mg mitomycin-c in 0.5 mlof solvent (water or 40% HPCD) was used. Eighteen rats were divided into3 groups. These groups of 6 rats each received the following injectionsat separate sites on the back: Group 1: Saline (0.5 ml) then saline (0.5ml) Saline (0.5 ml) then 40% HPCD (0.5 ml) 40% HPCD (0.5 ml) Group 2:Mitomycin-c in saline (0.5 ml) Mitomycin-c in 40% HPCD (0.5 ml) Group 3:Mitomycin-c in saline (0.5 ml) then saline (0.5 ml) Mitomycin-c insaline (0.5 ml) then 40% HPCD (0.5 ml)

[0096] Group 1 rats represent three different control injections.; Group2 rats test mitomycin-c diluted in saline versus mitomycin-c in 40%HPCD; and Group 3 rats test the effects of subsequent saline or HPCDinjection on mitomycin-c toxicity. HPCD had a degree of substitution of7. All injections were made into the skin and the accuracy of theintradermal injection was verified by local blanching of the skin at thetime of the injection. For Group 1 and 2, when sequential injectionswere made, the injection needle was left in place following the firstinjection and the second injection immediately followed the first . Thisinsured that the second injection was delivered to the same intradermalsite as the first. The results are shown in Table II. TABLE II Effectsof Cyclodextrin on Mitomycin-c Extravasation Toxicity-Lesion Diameter(cm) Day 1 Day 2 Day 3 Saline-Saline 0 ± 0 (6) 0 ± 0 (6) 0 ± 0 (6)Saline + 40% 0 ± 0 (6) 0.35 ± 0.09 (6) 0.26 ± 0.097 (6) HPCD 40% HPCD 0± 0 (6) 0.57 ± 0.14 (6) 0.6 ± 0.14 (6) mit-c + saline 0.95 ± 0.19 (6)1.3 ± 0.12 (6) 1.45 ± 0.15 (4)⁺ mit-c + 40% 0.36 ± 0.21 (6)* 0.53 ± 0.16(6) 0.58 ± 0.19 (4)⁺ HPCD mit-c then Saline 1.13 ± 0.05 (6) 1.5 ± 0.15(6) 1.52 ± 0.25 (3)⁺ mit-C then HPCD 1.28 ± 0.09 (6) 1.31 ± 0.27 (6) 0.4± 0.25 (3)⁺

[0097] Saline injection had no adverse effects when given intradermally.HPCD injections cause a small lesion whether it was administered after asaline injection (sal ne+40% HPCD=20% HPCD at the injection site) oralone 40% HPCD in 0.5 ml.) The lesion produced by HPCD appeared to beconcentration dependent and peaked at 4 days post injection. As the 20%HPCD lesion was small (3.5 mm) this dose of HPCD would appear to beoptimal for the injections.. However as all injections were done on thesame day and in as much as 0.40% HPCD was chosen, the following datashould be viewed with respect to the contribution of HPCD to the lesionsize. Mitomycin-c diluted in saline caused a 0.95 cm lesion by day Iwhich increased in size to 1.45 cm by day 6 post injection. By contrastwhen mitomycin-c was diluted in 40% HPCD, lesion size was reduced by ⅔each at each sampling time. The mitomycin-c-HPCD lesion wassignificantly smaller and it appears that mitomycin -C in HPCD canprevent greater than 50% the measurable extent of ulceration associatedwith extravasation of the chemotherapeutic agent.

[0098] Administration of mitomycin-c followed by HPCD appeared to havelittle beneficial effect on the size of lesions. This may be because (i)mitomycin-c rapidly interacts with tissue in a manner which cannot bereversed by HPCD or (II) complexation of mitomycin-c and HPCD does notoccur effectively in vivo. This latter possiblity is indicated by theobservation that during the intradermal injection, mitomycin-c (a bluecolor) was pushed to the periphery of the injection site by thesubsequent HPCD injection. The high viscosity of the HPCD displaced thedrug, rather than mixed with the mitomycin-c at the injection site. Thesubsequent injection of 40% HPCD was ineffective in preventingextravasation toxicity. As a result it is clear that prepartation ofmitomycin-c in HPCD is superior to attempts to mitigate ulcerationcaused by extravasated mitomycin-C.

EXAMPLE III Effects of HPCD on Mitomycin with Mannitol asExcipient—Extravasation Toxicity

[0099] Vials of mitomycin containing 10 mg of mannitol per mgmitomycin-c (Bristol Myers Oncology Division of Bristol Myers SquibbCompany [herein after referred to as MM, 1 Unit (U) MM=1 mg mitomycin Cand 10 mg mannitol]) were diluted to 1 mg mitomycin-c/ml H₂O or 40%HPCD. HPCD had a degree of substitution of 7. Vials were vortexed for 1min, allowed to sit at room temperature for 1 hr and were vortexed againfor 1 min. Five rats received an injection of 1 U MM/ml saline asdescribed above on one side and 1 UMM/ml 40% HPCD on the opposite sideof the back. The results are reported in Table III. TABLE III Effects onUlceration associated with Extravasation of HPCD - Mitomycin withMannitol as Measured by Lesion Diameter (cm) Day 1 Day 4Mitomycin-c/mannitol 0.865 ± 0.05 (5) 0.93 ± 0.064 (5) in H₂OMitomycin-c/mannitol 0.04 ± 0.035 (5)⁺ 0.13 ± 0.12 (5)⁺ in 40% HPCD

[0100] MM in H₂O caused lesions in all 5 of the rats tested. MM causedlesions in all 5 of the rats tested. The average lesion size was 0.865cm on day 1 post administration and increased to 0.93 cm on day 4 postadministration. By contrast, MM complexed with 40% HPCD caused no alesion in 4 of 5 rats tested. The one observed lesion measured 0.04 cmon day 1 and 0.013 cm on day 4 post administration.

EXAMPLE IV Preservation of Mytomycin-C Toxicity

[0101] The observations concerning toxicity as shown by change in bodyweight is in Study 2 and 3 is shown in Table IV. TABLE IV Effects ofIntradermal Administration of Mitomycin-c on Body Weight in Male RatsStudy 2 Day 0 Day 1 Day 4 Day 6 Group 1 (vehicles) 326 ± 5 335 ± 5 341 ±9 345 ± 6 Group 2 mitomycin-c 337 ± 6 351 ± 7 298 ± 5* 250 ± 2* (2.5 mgtotal dose) Group 3 mitomycin-c 343 ± 7 354 ± 9 286 ± 12* 261 ± 11* (2.5mg total dose) Study 3 Day 0 Day 1 Day 4 Group 1 MM 191 ± 7 185 ± 8 144± 5* (mitomycin-c-mannitol) 2.0 mg mitomycin-c dose

[0102] These studies were terminated at 4 to 6 days post administrationrespectively as the dose of mitomycin needed to produce consistent andreadily measurable lesions was very toxic to the rats. In Study 2 and3,, Mitomycin-c treated rats lost about 25% of their initial body weightover 6 and 4 days post administration respectively. All animalsreceiving MM had sever diarrhea, were cold to the touch and wereinactive Five of 12 mitomycin-treated study 2 rats died between days 4and 6. All study 3 rats died by day 6. The small initial size of thestudy 3 rats may have contributed to the increased mortality. In no casedid the systemic toxicity influence the formation skin lesion which wereapparent by day 1 prior to occurrence of any diarrhea or decrease inweight gain.

[0103] Systemic toxicity of the HPCD-mitomycin and HPCD-MM formulationswas not reduced as compared to equivalent doses of mitomycin-C in waterindicating that the toxicity required for effectiveness of mitomycin-cfor use as an anticancer agent is not impaired by formation of themitomycin-c-cyclodextrin complex or the mitomycin-c-cyclodextrin complexwith excipient.

EXAMPLE V Doxorubicin HPCD Formulation

[0104] Animals were injected with one of 5 solutions prepared asfollows: Solution A consisted of 2.5 mg mannitol and 0.2 gm HPCD in 0.5ml of saline. The mannitol dose is equal to that used in the doxorubacincommercial vehicle and the HPCD was 20% weight/volume (of saline).Solution B consisted of 2 mg doxorubacin and 2.5 mg mannitol/0.5 mlsaline (hereafter referred to as doxorubacin in commercial vehicle).Solution C consisted of 2 mg doxorubacin, 2.5 mg mannitol and 0.2 gmHPCD in 0.5 ml saline hereafter referred to as doxorubacin in 20% HPCD).All HPCD had a degree of substitution of 7.

Animal Use

[0105] Male Charles Rivers CD (Sprague-Dawley) rats were anesthetizedwith metaphane (inhalant), marked for continuous identification andweighed. The hair on the mid-section of their back was shaved, the skinwas thoroughly scrubbed with 70% ethanol and one of the aforementioned 5solutions was administered by a single intradermal injection using asterile 1 cc tuberculin syringe and a 27 gauge needle. Eight rats weretreated per group.

[0106] At 1, 3, 6, 13 and 20 days after the injection, rats wereweighed, the size of the lesion was measured, the lesion was describedand the general health of the rats was assessed and recorded. Lesiondiameter was determined by measuring the greatest and least extent ofthe lesion and the average of the 2 measurements was reported. Themeasurement of lesions and inspection of animals was done withoutanesthesia.

Results

[0107] Body Weight

[0108] The effects of intradermal injection of 20% HPCD and doxorubacinon body weight in adult male rats is depicted in Table 1. As we hadpreviously reported, 20% HPCD has no effect on body weight as animalscontinued to gain weight throughout the sampling period. This is theexpected weight response of young adult male rats. Treatment withdoxorubacin in commercial vihicle (CV) had no adverse effect on bodyweight and treatment with doxorubacin in 20% HPCD only modestly reducedthe rate of weight gain in rats. Indeed, this latter group of ratsappeared to gain weight normally through the 1st post-inject on week,then showed a slight decline in the rate of weight gain thereafter. Allanimals treated intradermally with doxorubacin appeared to be healthyand showed no adverse effects of the drug, other than the skin lesions,as intended.

[0109] Lesion Size

[0110] The effects of intradermal administration of doxorubacin onlesion size is depicted in Table 3. Intradermal injection of 0.5 ml of20% HPCD caused no effect in 7 of 8 rats tested. The remaining oneanimal developed a small lesion (0.3 cm diameter) which was observed onday 3 and 6 and which had healed completely by day 13 post injection.This observation is consistant with previous observations. Doxorubacinin CV caused necrotic lesions of the skin in all 8 rats tested whichpersisted throughout the observation period. The lesions were evident byday 3, peaked in diameter at 0.73±0.04 cm on day 6 and were slightlyreduced in size on day 13 and 20.

[0111] Doxorubicin in 20% HPCD showed a different response. On day 3only 4 of 8 rats had shown lesions, on days 6 and 13, 6 of 8 ratsexhibited lesions and on day 20, 4 of 8 rats had lesions. In theDoxorubacin in 20% HPCD group, 4 of the rats showed lesions thatpersisted through day 20. Two rats failed to exhibit lesions at anysampling time. The final two rats, showed small lesions which firstappeared by day 6, were present at day 13 and were completely healed byday 20. As a result, the diameter of the lesions produced were lower inthe Doxorubicin-20% HPCD group than in the Doxorubicin-in CV group ateach sampling time from day 3 to day 20.

[0112] Description of Lesions

[0113] For 7 of 8 rats injected with the vehicle, no lesion formed andthere was no evidence of an injection effect by the 1st day afterinjection. In the single animal which showed a lesion, a small, brown(necrotic) area was evident by day 3, but had healed by day 13.

[0114] For animals injected with doxorubacin in c.v., rats exhibited atthe time of the injection and at 1 day post-injection, a red coloredarea of the skin indicative of the deposition of the red coloreddoxorubacin. On the 1st post-injection day, the center of this reddenedarea was brown (necrotic) in 4 of 8 rats, but it was too small tomeasure. By day 3 post-injection, lesions had formed in all 8 rats andscabs had covered the damaged tissue. These scabs were well defined,persisted through the remainder of the study and were used to measurethe extent of the lesions.

[0115] Animals injected intradermally with doxorubacin formulated in 20%HPCD showed 2 subgroups. The first subgroup of 4 rats showed lesionswhich were similar in their progression and size to those seen in thedoxorubacin-c.v. group. That is, these animals showed red coloration atthe injection site on day one and exhibited lesions with scabs by day 3postinjection. By contrast, the second subgroup, which consisted of 2animals which did not develop lesion and 2 animals which developedsmall, rapidly healing lesions, showed a different response toinjection. First at one day after injection, the red coloration (drug)at the injection site was either non-existent or very faint. Thereafter,2 animals failed to develop skin lesions, and 2 animals exhibitedlesions which were small in size and rapidly healed. An example of thislatter, small lesion subgroup is animal #13, which on day 4 of the dayof the photograph, a red area was noted, but no lesion was present. Thisrat would develop a small lesion which was present on day 6 smaller onday 13 and completely healed by day 20.

Brief Interpretation of Data

[0116] From the data presented here and from my previous report, itappears that HPCD may be effective in reducing skin lesion size and theincidence of skin lesions by dispersing the complexed drug from theinjection site. In our previous study, we noted that lesions which formfollowing intradermal injection were more diffuse in nature whenmitomycin was formulated in HPCD versus commercial vehicle. In thepresent study, we found two evidences for the same phenomena. First, atone day following doxorubacin-HPCD injections, one-half of theinjected-rats failed to exhibit or showed only faint evidence of the redcolor associated with drug deposition. These animals were either lesionfree or subsequently formed only small lesions. TABLE V Days PostInjection Treatment* 0 3 6 13 20 HPCD/ 0  0.03 ± 0.03 ± 0 0 vehicle 0.03 0.04 Doxorubicin/ 0  0.63 ± 0.73 ± 0.66 ± 0.53 ± vehicle  0.040.04 0.03 0.04 Doxorubicin/ 0 0.375 ± 0.59 ± 0.44 ±  0.3 ± 20% HPCD 0.14 0.14 0.12 0.12

EXAMPLE VI Taxol Formulations of HPCD

[0117] Solutions for Injection

[0118] Animals were injected with one of the following solutions.Solution A consisted of 20% (w/v) of HPCD and represented the vehiclefor injection. Solution B consisted of a 50% ethanol solution of Taxol(1.25 mg/0.5 ml; hereafter referred to as Taxol in CV). Solution Cconsisted of 20% HPCD in ethanol/water (1/1, w/v; hereafter referred toas Taxol in HPCD). HPCD had a degree of subsitution of 7.

[0119] Male Charles Rivers CD rat eight rats per group were prepared andinjected as in Example V with a single intradermal injection of theindicated solution using a sterile 1 cc tuberculin syringe and a 27 gneedle. At 1, 3, and 7 days after the injection, rats were weighed, thesize of the lesion was determined, the lesions were described and thegeneral health of the rats was assessed and recorded.

[0120] Body Weight and General Health

[0121] The effects of Taxol administration on body weight is depicted inTable VI. All animals showed an increase in body weight following theinjection. The range of increase did not differ significantly betweengroups. These data indicate that the drugs were well tolerated by theanimals regardless of the vehicle used for the injection. Additionally,the animals appeared to be in good health and no abnormalities, otherthan the induced lesions, were observed.

[0122] Lesion Size

[0123] The effects of Taxol injection intradermally on lesiforminglesions of the skin are shown in Table 2. The 20% HPCD vehicle itself,caused no lesions. Taxol in CV caused lesions of 1.52±0.4 cm diameter byday 1, in all 8 rats injected, and the size of the lesions remained thesame through the remaining sampling periods. When formulated in HPCD,Taxol caused no lesions by day 1, and on days 3 and 7, six of 8 injectedrats showed lesions. The lesion size was reduced to ⅓ of that observedin Taxol-CV injected rats on both day 3 and 7.

[0124] Description of Lesions

[0125] The lesions produced by Taxol in CV were necrotic lesions whichdestroyed the skin at the injection site a manner which clearly relatedto the deposition of drug at the injection site. On day one, the lesionswere characterized by a large white center with a red halo around it.The lesions were very consistent in diameter as reflected in the smallstandard error in the data for the Taxol-HPCD group (see Table ). By daythree, lesions were maximal in size, were fully necrotic and hadscabbed. Little change occurred through day 7. When formulated in HPCD,Taxol failed to cause lesions on day 1; at this time, 5 of 8 rats showedevidence of redness at the site of deposition of the drug. On day 3, thelesions observed were similar to these seen in the Taxol-CV group, butwere smaller in size by ⅔. On day 7 all lesions were well healed andagain at this time were smaller in size than those seen in the Taxol-CVgroup.

[0126] The results of these studies indicate that HPCD exerts aprotective effect on skin when Taxol is deposited into an intradermalsite. Indeed, this effect is substantial, resulting in a ⅔ reduction inlesion size. TABLE VI Treatment Day 1 Day 3 Day 7 Vehicle 0 0 0 Taxol CV1.52 ± 0.04 1.58 ± 0.05 1.54 ± 0.04 Taxol HPCD 0 0.52 ± 0.12 0.52 ± 0.12

[0127] The compositions of matter according to the invention offerseveral advantages over the existing formulations of active compoundsadministered parenterally, especially intravenously. By reducingtoxicities associated with the use of these active compounds, it may bepossible to reduce the volume of the formulation in solution that isadministered to the patient without altering the effective dose of theactive compound. Thus within the spirit of the invention are improvedformulations and methods of using the same when administering suchformulations to patients. As mentioned herein above a number ofexcipients may be appropriate for use in the formulations which comprisethe composition according to the invention. The inclusion of excipientsand the optimization of their concentration for their expectedcharacteristics such as for example ease of handling or as carrieragents will be understood by those ordinarily skilled in the art not todepart from the spirit of the invention as described herein and claimedhereinbelow.

I claim:
 1. A composition of matter comprising an anti-ulcerationeffective amount of a substituted cyclodextrin compound and a cytotoxicdrug.
 2. The composition of matter of claim 1 wherein the ccytotoxicdrug is an anti-cancer drug that is soluble in aqueous solution.
 3. Thecomposition of claim 2 further comprising an excipient .
 4. Thecomposition of matter of claim 2 wherein said anticancer drug isselected from the group consisting of dactinomycin, dacarbazine,daunorubicin, doxorubicin, vincristine sulphate, vinblastine sulphate,mithramycin, mitomycin C, and streptozocin.
 5. The composition of matterof claim 4 further comprising an excipient.
 6. The composition of matterof claim 3 wherein said excipient is mannitol.
 7. The composition ofmatter of claim 5 wherein said excipient is mannitol.
 8. The compositionof matter of claim 6 wherein said anticancer drug soluble in aqueoussolution is mitomycin C.
 9. The composition of matter of claim 6 whereinsaid anticancer drug soluble in aqueous solution is doxorubicin.
 10. Thecomposition of matter of claim 6 wherein said anticancer drug soluble inaqueous solution is daunorubicin.
 11. The composition of matter of claim6 wherein said anticancer drug soluble in aqueous solution is bleomycin.12. The composition of matter of claim 6 wherein said anticancer drugsoluble in aqueous solution is vincristine sulphate
 13. The compositionof matter of claim 6 wherein said anticancer drug soluble in aqueoussolution is vinblastine sulphate.
 14. A method for reducing thelikelihood of ulceration or irritation in a subject in need ofparenteral treatment with a cytotoxic compound that has the potentialfor causing ulceration when extravasated or irritation, comprisingadministering to such subjects a preparation comprising an aqueoussolution of at least one cytotoxic compound that has the potential forcausing ulceration when extravasated or irritation and ananti-ulceration effective or anti-irritation effective amount of asubstituted cyclodextrin compound.
 15. The method of claim 14 whereinthe cytotoxic drug is an anti-cancer drug that is soluble in aqueoussolution.
 16. The method of claim 15 wherein said preparation farthercomprises an excipient.
 17. The method of claim 14 wherein saidanticancer drug is selected from the group consisting of dactinomycin,dacarbazine, daunorubicin, doxorubicin, vincristine sulphate,vinblastine sulphate, mithramycin, mitomycin C, and streptozocin. 18.The method of claim 17 wherein said preparation further comprises anexcipient.
 19. The method of claim 18 wherein said excipient ismannitol.
 20. The method of claim 15 wherein said excipient is mannitol.21. The composition of matter. of claim 16 wherein said anticancer drugsoluble in aqueous solution is mitomycin C.
 22. The composition ofmatter of claim 16 wherein said anticancer drug soluble in aqueoussolution is doxorubicin.
 23. The method claim 16 wherein said anticancerdrug soluble in aqueous solution is daunorubicin.
 24. The method ofclaim 16 wherein said anticancer drug soluble in aqueous solution isbleomycin.
 25. The method of claim 16 wherein said anticancer drugsoluble in aqueous solution is vincristine sulphate
 26. The method ofclaim 16 wherein said anticancer drug soluble in aqueous solution isvinblastine sulphate.
 27. A composition of matter comprising ananti-ulceration effective or anti irritation effective amount of ahydroxypropyl substituted cyclodextrin compound having a degree ofsubstitution of 5 to 10 and a cytotoxic drug.
 28. A method for reducingulceration or irritation in a subject in need of parenteral treatmentwith a cytotoxic compound such as an anti-cancer compound that has thepotential for causing irritation or ulceration when extravasated,comprising administering to such subject a preparation comprising anaqueous solution of at least one cytotoxic compound such as ananti-cancer drug that has the potential for causing irritation orulceration when extravasated and an anti-ulceration effective oranti-irritation effective amount of a hydroxypropyl substitutedcyclodextrin compound having a degree of substitution of 5 to 10.